Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease

BACKGROUND AND AIMS: Resistance to single cytokine blockade, namely anti-TNF therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines IFN-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. METHODS: Using an adaptive immune-mediated colitis model, human colonic lymphocytes from IBD patients and multiple large clinical datasets, we investigate the effect of CDK9 inhibitors on cytokine production and gene expression in colonic CD4+ T cells and link these genetic modules to clinical response in patients with IBD. RESULTS: Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from IBD patients, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. CONCLUSION: Collectively, our findings reveal CDK9 as a potential target for anti-TNF resistant IBD, which has the potential for rapid translation to the clinic

Uso de la radioterapia externa como parte del manejo terapéutico de los pacientes con diagnóstico de retinoblastoma: experiencia en el Servicio de Oncología del Hospital Nacional de Niños, durante el periodo de enero del 2009 a diciembre del 2015

Tesis (doctorado académico en radioterapia)--Universidad de Costa Rica. Sistema de Estudios de Posgrado, 2016UCR::Vicerrectoría de Investigación::Sistema de Estudios de Posgrado::Salud::Especialidad en Radioterapi

Likes and dislikes powerpoint

Ppt describing various likes and dislike

Powerpoint on key sentences, greetings/asking name/occupation/nationality in mandarin chinese

Review of key sentences for giving personal information in mandarin chines

Psychosomatic and physical responses to a multi-component stress management program among teaching professionals: a randomized study of cognitive behavioral intervention (CB) with complementary and alternative medicine (CAM) approach

Background: The present study aims to assess psychosomatic and physical responses to a multi-component stress management program with the use of CAM and CB approaches among teaching professionals in Hong Kong. Method: A random controlled trial (RCT) was used to compare between CB group (n = 26) and the CAM-CB group (n = 30). Interventions were administered for 1.5 h once a week for eight consecutive weeks. A self-administered questionnaire including perceived stress scale (PSS) and frequency of psychosomatic symptoms were measured at baseline (T1), immediate after the program (T2), and 4 weeks after the program (T3). Physical parameters were measured at T1 and T2. Result: A reduction of 23% in PSS was observed in the CB group, while the CAM-CB group yielded 18% reductions in PSS from T1 to T3 [F(2,108) = 3.099; p = .049]. No significant interactions were observed in the frequency of psychosomatic symptoms and physical parameters. However, a significant downward time trend was observed (p \u3c .001) and larger percentage changes in physical responses were shown in the CAM-CB group than CB group. Conclusion: Clinical evidence of both the CAM-CB and CB program has been demonstrated in the current study and both approaches are easy to be self-implemented. The CAM technique might serve as an alternative choice for self-administered stress management to replace the additional time needed for professional follow-up contacts. It might further improve some physical responses such as handgrip strength and resting heart rate, which are associated with better psychosomatic health and better occupational stress management

Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease

BACKGROUND & AIMS: Resistance to single cytokine blockade, namely anti-tumor necrosis factor (TNF) therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines interferon (IFN)-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. METHODS: Using an adaptive immune-mediated colitis model, human colonic lymphocytes from patients with IBD and multiple large clinical datasets, we investigate the effect of cyclin-dependent kinase 9 (CDK9) inhibitors on cytokine production and gene expression in colonic CD4(+) T cells and link these genetic modules to clinical response in patients with IBD. RESULTS: Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4(+) T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from patients with IBD, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. CONCLUSION: Collectively, our findings reveal CDK9 as a potential target for anti-TNF-resistant IBD, which has the potential for rapid translation to the clinic